title: Selective inhibition of tumor necrosis factor-α converting enzyme attenuates liver toxicity in a murine model of concanavalin A induced auto-immune hepatitis.
abstract: Emerging evidence suggest that tumor necrosis factor (TNF)-α plays a major role in pathogenesis of auto-immune hepatitis (AIH) induced liver injury. Blockade of TNF-α synthesis or bio-activity protects against experimental AIH. TNF-α converting enzyme (TACE) is a member of the ADAM (a disintegrin and metalloproteinase) family which processes precursor TNF-α to release soluble TNF-α. We hypothesized that selective inhibition of TACE might protect AIH. To investigate this, we studied the effects of a selective TACE inhibitor DPC-333 on murine model of liver injury and fibrosis induced with concanavalin A (Con A). Pre-treatment with DPC-333 significantly suppressed plasma alanine transaminase, aspartate transaminase and cytokines such as TNF-α, interferon (IFN)-γ, interleukin (IL)-2 and IL-6 levels due to acute Con A challenge. Interestingly; DPC-333 inhibited liver poly (ADP-ribose) polymerase (PARP)-1 activity which was associated with reduced number of necrotic hepatocytes in histological examination and mortality associated with Con A. In fibrosis study, repeated Con A administration significantly up-regulated liver collagen deposition as assessed by measurement of hydroxyproline content which was further confirmed in liver histology with Masson's trichrome staining. Treatment with 30mg/kg of DPC-333 was able to suppress liver hydroxyproline and fibrous tissue proliferation which corroborated well with inhibition in expression of pro-fibrotic genes such as tissue inhibitor of metalloproteinase (TIMP)-1 and transforming growth factor (TGF)-β1. These observations suggest that selective TACE inhibition is an effective approach for the treatment of both immune mediated hepatic inflammation and fibrosis.
authors.affiliation: Dept. of Pharmacology, Zydus Research Centre, Moraiya, Ahmedabad, Gujarat, India.
authors.forename: Manoranjan
authors.initials: M
authors.lastname: Sharma
authors.forename: Jogeswar
authors.initials: J
authors.lastname: Mohapatra
authors.forename: Umar
authors.initials: U
authors.lastname: Malik
authors.forename: Akshaya
authors.initials: A
authors.lastname: Wagh
authors.forename: Anuj
authors.initials: A
authors.lastname: Singh
authors.forename: Hiren M
authors.initials: HM
authors.lastname: Patel
authors.forename: Dheerendra
authors.initials: D
authors.lastname: Pandey
authors.forename: Shekhar
authors.initials: S
authors.lastname: Kadam
authors.forename: Gourang B
authors.initials: GB
authors.lastname: Shah
authors.forename: Abhijit
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Mukul R
authors.initials: MR
authors.lastname: Jain
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000072198:ADAM17 Protein; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002478:Cells, Cultured; D003208:Concanavalin A / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005355:Fibrosis; D019693:Hepatitis, Autoimmune / Q000188:drug therapy* / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000008:administration & dosage* / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: C476910:BMS561392; D016207:Cytokines; D018836:Inflammation Mediators; D011804:Quinolines; D019715:Tissue Inhibitor of Metalloproteinase-1; D003208:Concanavalin A; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
keywords: Autoimmune hepatitis; Concanavalin A; PARP-1; TNF-α; TNF-α converting enzyme